This invention is directed to compounds that are useful in treating diseases associated with metalloprotease activity, particularly zinc metalloprotease activity. The invention is also directed to pharmaceutical compositions comprising the compounds, and to methods of treating metalloprotease-related maladies using the compounds or the pharmaceutical compositions.
A number of structurally related metalloproteases effect the breakdown of structural proteins. These metalloproteases often act on the intercellular matrix, and thus are involved in tissue breakdown and remodeling. Such proteins are referred to as metalloproteases or MPs.
There are several different families of MPs, classified by sequence homology, disclosed in the art. These MPs include Matrix-Metallo Proteases (MMPs); zinc metalloproteases; many of the membrane bound metalloproteases; TNF converting enzymes; angiotensin-converting enzymes (ACEs); disintegrins, including ADAMs (See Wolfsberg et al, 131 J. Cell Bio. 275-78 October, 1995); and the enkephalinases. Examples of MPs include human skin fibroblast collagenase, human skin fibroblast gelatinase, human sputum collagenase, aggrecanse and gelatinase, and human stromelysin. Collagenases, stromelysin, aggrecanase and related enzymes are thought to be important in mediating the symptomatology of a number of diseases.
Potential therapeutic indications of MP inhibitors have been discussed in the literature. See, for example, U.S. Pat. No. 5,506,242 (Ciba Geigy Corp.) and U.S. Pat. No. 5,403,952 (Merck and Co.); the following PCT published application: WO 96/06074 (British Bio Tech Ltd.); WO 96/00214 (Ciba Geigy), WO 95/35275 (British Bio Tech Ltd.), WO 95/35276 (British Bio Tech Ltd.), WO 95/33731 (Hoffman-LaRoche), WO 95/33709 (Hoffman-LaRoche), WO 95/32944 (British Bio Tech Ltd.), WO 95/26989 (Merck), WO 9529892 (DuPont Merck), WO 95/24921 (Inst. Opthamology), WO 95/23790 (SmithKline Beecham), WO 95/22966 (Sanofi Winthrop), WO 95/19965 (Glycomed), WO 95 19956 (British Bio Tech Ltd), WO 95/19957 (British Bio Tech Ltd.), WO 95/19961 (British Bio Tech Ltd.), WO 95/13289 (Chiroscience Ltd.), WO 95/12603 (Syntex), WO 95/09633 (Florida State Univ.), WO 95/09620 (Florida State Univ.), WO 95/04033 (Celitech), WO 94/25434 (Celltech), WO 94/25435 (Celltech); WO 93/14112 (Merck), WO 94/0019 (Glaxo), WO 93/21942 (British Bio Tech Ltd.), WO 92/22523 (Res. Corp. Tech Inc.), WO 94/10990 (British Bio Tech Ltd.), WO 93/09090 (Yamanouchi); British patents GB 2282598 (Merck) and GB 2268934 (British Bio Tech Ltd.); published European Patent Applications EP 95/684240 (Hoffman LaRoche), EP 574758 (Hoffman LaRoche) and EP 575844 (Hoffman LaRoche); published Japanese applications JP 08053403 (Fujusowa Pharm. Co. Ltd.) and JP 7304770 (Kanebo Ltd.); and Bird et al., J. Med. Chem., vol. 37, pp. 158-69 (1994).
Examples of potential therapeutic uses of MP inhibitors include rheumatoid arthritisxe2x80x94Mullins, D. E., et al., Biochim. Biophys. Acta. (1983) 695:117-214; osteoarthritisxe2x80x94Henderson, B., et al., Drugs of the Future (1990) 15:495-508; cancerxe2x80x94Yu, A. E. et al., Matrix Metalloproteinasesxe2x80x94Novel Targets for Directed Cancer Therapy, Drugs and Aging, Vol. 11(3), p. 229-244 (September 1997), Chambers, A. F. and Matrisian, L. M., Review: Changing Views of the Role of Matrix Metalloproteinases in Metastasis, J. of the Nat""l Cancer Inst., Vol. 89(17), p. 1260-1270 (September 1997), Bramhall, S. R., The Matrix Metalloproteinases and Their Inhibitors in Pancreatic Cancer, Internat""l J. of Pancreatology, Vol. 4, p. 1101-1109 (May 1998), Nemunaitis, J. et al., Combined Analysis of Studies of the Effects of the Matrix Metalloproteinase Inhibitor Marimastat on Serum Tumor Markers in Advanced Cancer: Selection of a Biologically Active and Tolerable Dose for Longer-term Studies, Clin. Cancer Res., Vol 4, p. 1101-1109 (May 1998), and Rasmussen, H. S. and McCann, P. P, Matrix Metalloproteinase Inhibition as a Novel Anticancer Strategy: A Review with Special Focus on Batimastat and Marimastat, Pharmacol. Ther., Vol 75(1), p. 69-75 (1997); the metastasis of tumor cellsxe2x80x94ibid, Broadhurst, M. J., et al., European Patent Application 276,436 (published 1987), Reich, R., et al., Cancer Res., Vol. 48, p. 3307-3312 (1988); multiple sclerosisxe2x80x94Gijbels et al., J. Clin. Invest., vol. 94, p. 2177-2182 (1994); and various ulcerations or ulcerative conditions of tissue. For example, ulcerative conditions can result in the cornea as the result of alkali burns or as a result of infection by Pseudomonas aeruginosa, Acanthamoeba, Herpes simplex and vaccinia viruses. Other examples of conditions characterized by undesired metalloprotease activity include periodontal disease, epidermolysis bullosa, fever, inflammation and scleritis (e.g., DeCicco et al., World Patent Publication WO 95/29892 published Nov. 9, 1995).
In view of the involvement of such metalloproteases in a number of disease conditions, attempts have been made to prepare inhibitors to these enzymes. A number of such inhibitors are disclosed in the literature. Examples include U.S. Pat. No. 5,183,900, issued Feb. 2, 1993 to Galardy; U.S. Pat. No. 4,996,358, issued Feb. 26, 1991 to Handa, et al.; U.S. Pat. No. 4,771,038, issued Sep. 13, 1988 to Wolanin, et al.; U.S. Pat. No. 4,743,587, issued May 10, 1988 to Dickens, et al., European Patent Publication No. 575,844, published Dec. 29, 1993 by Broadhurst, et al.; International Patent Publication No. WO 93/09090, published May 13, 1993 by Isomura, et al.; World Patent Publication 92/17460, published Oct. 15, 1992 by Markwell et al.; and European Patent Publication No. 498,665, published Aug. 12, 1992 by Beckett, et al.
It would be advantageous to inhibit these metalloproteases in treating diseases related to unwanted metalloprotease activity. Though a variety of MP inhibitors have been prepared, there is a continuing need for potent matrix metalloprotease inhibitors useful in treating diseases associated with metalloprotease activity.
The invention provides compounds which are potent inhibitors of metalloproteases and which are effective in treating conditions characterized by excess activity of these enzymes. In particular, the present invention relates to compounds having a structure according to the following Formula (I): 
wherein:
(A) R1 is selected from xe2x80x94OH and xe2x80x94NHOH;
(B) R2 is selected from hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and halogen;
(C) R3 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
(D) R4 is xe2x80x94(CR7R7xe2x80x2)kxe2x80x94Xxe2x80x94(CR8R8xe2x80x2)lxe2x80x94Exe2x80x94A where:
(1) k is from 0 to about 4;
(2) l is from 0 to about 4;
(3) each of R7, R7xe2x80x2, R8, and R8xe2x80x2, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, and haloalkyl;
(4) X is selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O2)xe2x80x94, xe2x80x94N(R9)xe2x80x94, xe2x80x94N(COR9)xe2x80x94, xe2x80x94N(CO2R9)xe2x80x94, xe2x80x94N(CONR9R9xe2x80x2)xe2x80x94, and xe2x80x94N(SO2R9)xe2x80x94, where (i) each R9 and R9xe2x80x2, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R9 and R9xe2x80x2, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
(5) E is selected from a covalent bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O2)xe2x80x94, xe2x80x94N(R10)xe2x80x94, xe2x80x94N(COR10)xe2x80x94, xe2x80x94N(CO2R10)xe2x80x94, xe2x80x94N(CONR10R10xe2x80x2)xe2x80x94, and xe2x80x94N(SO2R10)xe2x80x94, where (i) each R10 and R10xe2x80x2, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl, or (ii) R10 and R10xe2x80x2, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; provided that when l=0, E is a covalent bond; and
(6)
(a) A is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; or
xe2x80x83(b) A, together with R7, R7xe2x80x2, R8, R8xe2x80x2, R9, R9xe2x80x2, R10, or R10xe2x80x2, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
(E) R5 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl;
(F) R6 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and hydroxyl; provided that when k greater than 0, R6 is xe2x80x94OH and when k=0, R6 is not xe2x80x94OH;
(G) G is selected from xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R11)xe2x80x94, xe2x80x94C(R11)xe2x95x90C(R11xe2x80x2)xe2x80x94, xe2x80x94Nxe2x95x90C(R11)xe2x80x94, and xe2x80x94Nxe2x95x90Nxe2x80x94, where each R11 and R11xe2x80x2, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
(H) Z is selected from:
(1) cycloalkyl and heterocycloalkyl;
(2) xe2x80x94Lxe2x80x94(CR12R12xe2x80x2)axe2x80x94R13 where:
(a) a is from 0 to about 4;
(b) L is selected from xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94SO2xe2x80x94;
(c) each R12 and R12xe2x80x2, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; and
(d) R13 is selected from hydrogen, aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl; and, if L is xe2x80x94Cxe2x89xa1Cxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94, then R13 may also be selected from xe2x80x94CON(R14R14xe2x80x2) where (i) R14 and R14xe2x80x2 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or (ii) R14 and R14xe2x80x2, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms;
(3) xe2x80x94NR15R15xe2x80x2 where:
(a) R15 and R15xe2x80x2 each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl and xe2x80x94C(O)xe2x80x94Qxe2x80x94(CR16R16xe2x80x2)bxe2x80x94R17 where:
(i) b is from 0 to about 4;
(ii) Q is selected from a covalent bond and xe2x80x94N(R18)xe2x80x94; and
(iii) each R16 and R16xe2x80x2, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; each R17 and R18 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or R17 and R18, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; or R15 and R18, together with the nitrogen atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 2 to 3 are heteroatoms; or
(b) R15 and R15xe2x80x2, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms; and
(4) 
xe2x80x83where:
(a) Exe2x80x2 and Mxe2x80x2 are independently selected from xe2x80x94CHxe2x80x94 and xe2x80x94Nxe2x80x94;
(b) Lxe2x80x2 is selected from xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R20)xe2x80x94, xe2x80x94C(R20)xe2x95x90C(R20xe2x80x2)xe2x80x94, Nxe2x95x90C(R20)xe2x80x94, and xe2x80x94Nxe2x95x90Nxe2x80x94, where each R20 and R20xe2x80x2, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl;
(c) c is from 0 to about 4;
(d) each R19 and R19xe2x80x2, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy;
(e) Axe2x80x2 is selected from a covalent bond, xe2x80x94Oxe2x80x94, xe2x80x94SOdxe2x80x94, xe2x80x94C(O)xe2x80x94, C(O)N(R21)xe2x80x94, xe2x80x94N(R21)xe2x80x94, and xe2x80x94N(R21)C(O)xe2x80x94; where d is from 0 to 2 and R21 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; and
(f) Gxe2x80x2 is xe2x80x94(CR22R22xe2x80x2)exe2x80x94R23 where e is from 0 to about 4; each R22 and R22xe2x80x2, when present, is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy; and R23 is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; or R21 and R23, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms; or R20 and R23, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 atoms of which 1 to 3 are heteroatoms;
or an optical isomer, diastereomer or enantiomer for Formula (I), or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof.
This invention also includes optical isomers, diastereomers and enantiomers of the formula above, and pharmaceutically-acceptable salts, biohydrolyzable amides, esters, and imides thereof.
The compounds of the present invention are useful for the treatment of diseases and conditions which are characterized by unwanted metalloprotease activity. Accordingly, the invention further provides pharmaceutical compositions comprising these compounds. The invention still further provides methods of treatment for metalloprotease-related maladies.
The following is a list of definitions for terms used herein.
xe2x80x9cAcylxe2x80x9d or xe2x80x9ccarbonylxe2x80x9d is a radical formed by removal of the hydroxy from a carboxylic acid (i.e., Rxe2x80x94C(xe2x95x90O)xe2x80x94). Preferred acyl groups include (for example) acetyl, formyl, and propionyl.
xe2x80x9cAlkylxe2x80x9d is a saturated hydrocarbon chain having 1 to 15 carbon atoms, preferably 1 to 10, more preferably 1 to 4 carbon atoms. xe2x80x9cAlkenexe2x80x9d is a hydrocarbon chain having at least one (preferably only one) carbon-carbon double bond and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms. xe2x80x9cAlkynexe2x80x9d is a hydrocarbon chain having at least one (preferably only one) carbon-carbon triple bond and having 2 to 15 carbon atoms, preferably 2 to 10, more preferably 2 to 4 carbon atoms. Alkyl, alkene and alkyne chains (referred to collectively as xe2x80x9chydrocarbon chainsxe2x80x9d) may be straight or branched and may be unsubstituted or substituted. Preferred branched alkyl, alkene and alkyne chains have one or two branches, preferably one branch. Preferred chains are alkyl. Alkyl, alkene and alkyne hydrocarbon chains each may be unsubstituted or substituted with from 1 to 4 substituents; when substituted, preferred chains are mono-, di-, or tri-substituted. Alkyl, alkene and alkyne hydrocarbon chains each may be substituted with halo, hydroxy, aryloxy (e.g., phenoxy), heteroaryloxy, acyloxy (e.g., acetoxy), carboxy, aryl (e.g., phenyl), heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, amido, acylamino, keto, thioketo, cyano, or any combination thereof. Preferred hydrocarbon groups include methyl, ethyl, propyl, isopropyl, butyl, vinyl, allyl, butenyl, and exomethylenyl.
Also, as referred to herein, a xe2x80x9clowerxe2x80x9d alkyl, alkene or alkyne moiety (e.g., xe2x80x9clower alkylxe2x80x9d) is a chain comprised of 1 to 6, preferably from 1 to 4, carbon atoms in the case of alkyl and 2 to 6, preferably 2 to 4, carbon atoms in the case of alkene and alkyne.
xe2x80x9cAlkoxyxe2x80x9d is an oxygen radical having a hydrocarbon chain substituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e., xe2x80x94O-alkyl or xe2x80x94O-alkenyl). Preferred alkoxy groups include (for example) methoxy, ethoxy, propoxy and allyloxy.
xe2x80x9cArylxe2x80x9d is an aromatic hydrocarbon ring. Aryl rings are monocyclic or fused bicyclic ring systems. Monocyclic aryl rings contain 6 carbon atoms in the ring. Monocyclic aryl rings are also referred to as phenyl rings. Bicyclic aryl rings contain from 8 to 17 carbon atoms, preferably 9 to 12 carbon atoms, in the ring. Bicyclic aryl rings include ring systems wherein one ring is aryl and the other ring is aryl, cycloalkyl, or heterocycloakyl. Preferred bicyclic aryl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Aryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Aryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, aryloxy, alkoxy, heteroalkyloxy, carbamyl, methylenedioxy, heteroaryloxy, or any combination thereof. Preferred aryl rings include naphthyl, tolyl, xylyl, and phenyl. The most preferred aryl ring radical is phenyl.
xe2x80x9cAryloxyxe2x80x9d is an oxygen radical having an aryl substituent (i.e., xe2x80x94O-aryl). Preferred aryloxy groups include (for example) phenoxy, napthyloxy, methoxyphenoxy, and methylenedioxyphenoxy.
xe2x80x9cCycloalkylxe2x80x9d is a saturated or unsaturated hydrocarbon ring. Cycloalkyl rings are not aromatic. Cycloalkyl rings are monocyclic, or are fused, spiro, or bridged bicyclic ring systems. Monocyclic cycloalkyl rings contain from about 3 to about 9 carbon atoms, preferably from 3 to 7 carbon atoms, in the ring. Bicyclic cycloalkyl rings contain from 7 to 17 carbon atoms, preferably from 7 to 12 carbon atoms, in the ring. Preferred bicyclic cycloalkyl rings comprise 4-, 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Cycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Cycloalkyl may be substituted with halo, cyano, alkyl, heteroalkyl, haloalkyl, phenyl, keto, hydroxy, carboxy, amino, acylamino, aryloxy, heteroaryloxy, or any combination thereof. Preferred cycloalkyl rings include cyclopropyl, cyclopentyl, and cyclohexyl.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d is fluoro, chloro, bromo or iodo. Preferred halo are fluoro, chloro and bromo; more preferred typically are chloro and fluoro.
xe2x80x9cHaloalkylxe2x80x9d is a straight, branched, or cyclic hydrocarbon substituted with one or more halo substituents. Preferred are C1-C12 haloalkyls; more preferred are C1-C6 haloalkyls; still more preferred still are C1-C3 haloalkyls. Preferred halo substituents are fluoro and chloro.
xe2x80x9cHeteroatomxe2x80x9d is a nitrogen, sulfur, or oxygen atom. Groups containing more than one heteroatom may contain different heteroatoms.
xe2x80x9cHeteroalkylxe2x80x9d is a saturated or unsaturated chain containing carbon and at least one heteroatom, wherein no two heteroatoms are adjacent. Heteroalkyl chains contain from 2 to 15 member atoms (carbon and heteroatoms) in the chain, preferably 2 to 10, more preferably 2 to 5. For example, alkoxy (i.e., xe2x80x94O-alkyl or xe2x80x94O-heteroalkyl) radicals are included in heteroalkyl. Heteroalkyl chains may be straight or branched. Preferred branched heteroalkyl have one or two branches, preferably one branch. Preferred heteroalkyl are saturated. Unsaturated heteroalkyl have one or more carbon-carbon double bonds and/or one or more carbon-carbon triple bonds. Preferred unsaturated heteroalkyls have one or two double bonds or one triple bond, more preferably one double bond. Heteroalkyl chains may be unsubstituted or substituted with from 1 to 4 substituents. Preferred substituted heteroalkyl are mono-, di-, or tri-substituted. Heteroalkyl may be substituted with lower alkyl, haloalkyl, halo, hydroxy, aryloxy, heteroaryloxy, acyloxy, carboxy, monocyclic aryl, heteroaryl, cycloalkyl, heterocycloalkyl, spirocycle, amino, acylamino, amido, keto, thioketo, cyano, or any combination thereof.
xe2x80x9cHeteroarylxe2x80x9d is an aromatic ring containing carbon atoms and from 1 to about 6 heteroatoms in the ring. Heteroaryl rings are monocyclic or fused bicyclic ring systems. Monocyclic heteroaryl rings contain from about 5 to about 9 member atoms (carbon and heteroatoms), preferably 5 or 6 member atoms, in the ring. Bicyclic heteroaryl rings contain from 8 to 17 member atoms, preferably 8 to 12 member atoms, in the ring. Bicyclic heteroaryl rings include ring systems wherein one ring is heteroaryl and the other ring is aryl, heteroaryl, cycloalkyl, or heterocycloalkyl. Preferred bicyclic heteroaryl ring systems comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Heteroaryl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Heteroaryl may be substituted with halo, cyano, nitro, hydroxy, carboxy, amino, acylamino, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy, heteroaryloxy, or any combination thereof. Preferred heteroaryl rings include, but are not limited to, the following: 
xe2x80x9cHeteroaryloxyxe2x80x9d is an oxygen radical having a heteroaryl substituent (i.e., xe2x80x94O-heteroaryl). Preferred heteroaryloxy groups include (for example) pyridyloxy, furanyloxy, (thiophene)oxy, (oxazole)oxy, (thiazole)oxy, (isoxazole)oxy, pyrmidinyloxy, pyrazinyloxy, and benzothiazolyloxy.
xe2x80x9cHeterocycloalkylxe2x80x9d is a saturated or unsaturated ring containing carbon atoms and from 1 to about 4 (preferably 1 to 3) heteroatoms in the ring. Heterocycloalkyl rings are not aromatic. Heterocycloalkyl rings are monocyclic, or are fused, bridged, or spiro bicyclic ring systems. Monocyclic heterocycloalkyl rings contain from about 3 to about 9 member atoms (carbon and heteroatoms), preferably from 5 to 7 member atoms, in the ring. Bicyclic heterocycloalkyl rings contain from 7 to 17 member atoms, preferably 7 to 12 member atoms, in the ring. Bicyclic heterocycloalkyl rings contain from about 7 to about 17 ring atoms, preferably from 7 to 12 ring atoms. Bicyclic heterocycloalkyl rings may be fused, spiro, or bridged ring systems. Preferred bicyclic heterocycloalkyl rings comprise 5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings. Heterocycloalkyl rings may be unsubstituted or substituted with from 1 to 4 substituents on the ring. Heterocycloalkyl may be substituted with halo, cyano, hydroxy, carboxy, keto, thioketo, amino, acylamino, acyl, amido, alkyl, heteroalkyl, haloalkyl, phenyl, alkoxy, aryloxy or any combination thereof. Preferred substituents on heterocycloalkyl include halo and haloalkyl. Preferred heterocycloalkyl rings include, but are not limited to, the following: 
As used herein, xe2x80x9cmammalian metalloproteasexe2x80x9d refers to the proteases disclosed in the xe2x80x9cBackgroundxe2x80x9d section of this application. The compounds of the present invention are preferably active against xe2x80x9cmammalian metalloproteasesxe2x80x9d, including any metal-containing (preferably zinc-containing) enzyme found in animal, preferably mammalian, sources capable of catalyzing the breakdown of collagen, gelatin or proteoglycan under suitable assay conditions. Appropriate assay conditions can be found, for example, in U.S. Pat. No. 4,743,587, which references the procedure of Cawston, et al., Anal. Biochem. (1979) 99:340-345; use of a synthetic substrate is described by Weingarten, H., et al., Biochem. Biophy. Res. Comm. (1984) 139:1184-1187. See also Knight, C. G. et al., xe2x80x9cA Novel Coumarin-Labelled Peptide for Sensitive Continuous Assays of the Matrix Metalloproteasesxe2x80x9d, FEBS Letters, Vol. 296, pp. 263-266 (1992). Any standard method for analyzing the breakdown of these structural proteins can, of course, be used. The present compounds are more preferably active against metalloprotease enzymes that are zinc-containing proteases which are similar in structure to, for example, human stromelysin or skin fibroblast collagenase. The ability of candidate compounds to inhibit metalloprotease activity can, of course, be tested in the assays described above. Isolated metalloprotease enzymes can be used to confirm the inhibiting activity of the invention compounds, or crude extracts which contain the range of enzymes capable of tissue breakdown can be used.
xe2x80x9cSpirocyclexe2x80x9d is an alkyl or heteroalkyl diradical substituent of alkyl or heteroalkyl wherein said diradical substituent is attached geminally and wherein said diradical substituent forms a ring, said ring containing 4 to 8 member atoms (carbon or heteroatom), preferably 5 or 6 member atoms.
While alkyl, heteroalkyl, cycloalkyl, and heterocycloalkyl groups may be substituted with hydroxy, amino, and amido groups as stated above, the following are not envisioned in the invention:
1. Enols (OH attached to a carbon-carbon double bond).
2. Amino groups attached to a carbon-carbon double bond (except for vinylogous amides).
3. More than one hydroxy, amino, or amido attached to a single carbon (except where two nitrogen atoms are attached to a single carbon atom and all three atoms are member atoms within a heterocycloalkyl ring).
4. Hydroxy, amino, or amido attached to a carbon that also has a halogen attached to it.
A xe2x80x9cpharmaceutically-acceptable saltxe2x80x9d is a cationic salt formed at any acidic (e.g., hydroxamic or carboxylic acid) group, or an anionic salt formed at any basic (e.g., amino) group. Many such salts are known in the art, as described in World Patent Publication 87/05297, Johnston et al., published Sep. 11, 1987 incorporated by reference herein. Preferred cationic salts include the alkali metal salts (such as sodium and potassium), and alkaline earth metal salts (such as magnesium and calcium) and organic salts. Preferred anionic salts include the halides (such as chloride salts), sulfonates, carboxylates, phosphates, and the like.
Such salts are well understood by the skilled artisan, and the skilled artisan is able to prepare any number of salts given the knowledge in the art. Furthermore, it is recognized that the skilled artisan may prefer one salt over another for reasons of solubility, stability, formulation ease and the like. Determination and optimization of such salts is within the purview of the skilled artisan""s practice.
A xe2x80x9cbiohydrolyzable amidexe2x80x9d is an amide of a hydroxamic acid-containing (i.e., R1 in Formula (I) is xe2x80x94NHOH) metalloprotease inhibitor that does not interfere with the inhibitory activity of the compound, or that is readily converted in vivo by an animal, preferably a mammal, more preferably a human subject, to yield an active metalloprotease inhibitor. Examples of such amide derivatives are alkoxyamides, where the hydroxyl hydrogen of the hydroxamic acid of Formula (I) is replaced by an alkyl moiety, and acyloxyamides, where the hydroxyl hydrogen is replaced by an acyl moiety (i.e., Rxe2x80x94C(xe2x95x90O)xe2x80x94).
A xe2x80x9cbiohydrolyzable hydroxy imidexe2x80x9d is an imide of a hydroxamic acid-containing metalloprotease inhibitor that does not interfere with the metalloprotease inhibitory activity of these compounds, or that is readily converted in vivo by an animal, preferably a mammal, more preferably a human subject to yield an active metalloprotease inhibitor. Examples of such imide derivatives are those where the amino hydrogen of the hydroxamic acid of Formula (I) is replaced by an acyl moiety (i.e., Rxe2x80x94C(xe2x95x90O)xe2x80x94).
A xe2x80x9cbiohydrolyzable esterxe2x80x9d is an ester of a carboxylic acid-containing (i.e., R1 in Formula (I) is xe2x80x94OH) metalloprotease inhibitor that does not interfere with the metalloprotease inhibitory activity of these compounds or that is readily converted by an animal to yield an active metalloprotease inhibitor. Such esters include lower alkyl esters, lower acyloxy-alkyl esters (such as acetoxymethyl, acetoxyethyl, aminocarbonyloxymethyl, pivaloyloxymethyl and pivaloyloxyethyl esters), lactonyl esters (such as phthalidyl and thiophthalidyl esters), lower alkoxyacyloxyalkyl esters (such as methoxycarbonyloxymethyl, ethoxycarbonyloxyethyl and isopropoxycarbonyloxyethyl esters), alkoxyalkyl esters, choline esters and alkyl acylamino alkyl esters (such as acetamidomethyl esters).
A xe2x80x9csolvatexe2x80x9d is a complex formed by the combination of a solute (e.g., a metalloprotease inhibitor) and a solvent (e.g., water). See J. Honig et al., The Van Nostrand Chemist""s Dictionary, p. 650 (1953). Pharmaceutically-acceptable solvents used according to this invention include those that do not interfere with the biological activity of the metalloprotease inhibitor (e.g., water, ethanol, acetic acid, N,N-dimethylformamide and others known or readily determined by the skilled artisan).
The terms xe2x80x9coptical isomerxe2x80x9d, xe2x80x9cstereoisomerxe2x80x9d, and xe2x80x9cdiastereomerxe2x80x9d have the standard art recognized meanings (see, e.g., Hawley""s Condensed Chemical Dictionary, 11th Ed.). The illustration of specific protected forms and other derivatives of the compounds of the instant invention is not intended to be limiting. The application of other useful protecting groups, salt forms, etc. is within the ability of the skilled artisan.
The subject invention involves compounds of Formula (I): 
where R1, R2, R3, R4, R5, R6, G and Z have the meanings described above. The following provides a description of particularly preferred moieties, but is not intended to limit the scope of the claims.
R1 is selected from xe2x80x94OH and xe2x80x94NHOH; preferably xe2x80x94OH.
R2 is selected from hydrogen, hydroxyl, alkoxy, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, and halogen; preferably hydrogen or alkyl, more preferably hydrogen.
R3 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; preferably hydrogen or alkyl, more preferably hydrogen.
R4 is xe2x80x94(CR7R7xe2x80x2)kxe2x80x94Xxe2x80x94(CR8R8xe2x80x2)lxe2x80x94Exe2x80x94A. Each of k and l is independently selected from 0, 1, 2, 3 or 4; preferably k is 0, 1, 2 or 3; preferably l is 0, 1 or 2. Each of R7, R7xe2x80x2, R8, and R8xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen and haloalkyl; preferably all are hydrogen.
X is selected from xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O)xe2x80x94, xe2x80x94S(O2)xe2x80x94, xe2x80x94N(R9)xe2x80x94, xe2x80x94N(COR9)xe2x80x94, xe2x80x94N(CO2R9)xe2x80x94, xe2x80x94N(CONR9R9xe2x80x2)xe2x80x94, and xe2x80x94N(SO2R9)xe2x80x94, where each R9 and R9xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl (preferably each R9 and R9xe2x80x2 is hydrogen), or (ii) R9 and R9xe2x80x2 together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms. Preferably X is xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(SO2R9), xe2x80x94N(COR9), xe2x80x94NCO2R9), where R9 is preferably lower alkyl or aryl.
E is selected from a covalent bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94S(O), xe2x80x94S(O2)xe2x80x94, xe2x80x94N(R10)xe2x80x94, xe2x80x94N(COR10)xe2x80x94, xe2x80x94(CO2R10)xe2x80x94, xe2x80x94N(CONR10R10xe2x80x2)xe2x80x94, and xe2x80x94N(SO2R10)xe2x80x94, where (i) each R10 and R10xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl (preferably each R10 and R10xe2x80x2 is hydrogen), or (ii) R10 and R10xe2x80x2 together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 ring atoms of which from 1 to 3 are heteroatoms. Preferably, E is covalent bond, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94N(SO2R10)xe2x80x94, xe2x80x94N(COR10), or xe2x80x94N(CO2R10)xe2x80x94, where R10 is preferably lower alkyl or aryl. When l=0, E is a covalent bond.
A is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; preferably A is alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl.
R5 is selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, and heterocycloalkyl; preferably hydrogen or lower alkyl; more preferably hydrogen.
R6 is selected from alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, cycloalkyl, heterocycloalkyl, and hydroxyl; preferably aryl, heteroaryl or hydroxyl. When k greater than 0, R6 is xe2x80x94OH and when k =0, R6 is not xe2x80x94OH.
G is selected from xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R11)xe2x80x94, xe2x80x94C(R11xe2x80x2)xe2x95x90C(R11xe2x80x2)xe2x80x94, xe2x80x94Nxe2x95x90C(R11)xe2x80x94, and xe2x80x94Nxe2x95x90Nxe2x80x94; in a preferred embodiment, G is xe2x80x94Sxe2x80x94 or xe2x80x94C(R11)xe2x95x90C(R11xe2x80x2)xe2x80x94. Each R11 and R11xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; preferably at least one of R11 and R11xe2x80x2 is hydrogen, more preferably both are hydrogen.
Z is selected from cycloalkyl and heterocycloalkyl; xe2x80x94Lxe2x80x94(CR12R12xe2x80x2)axe2x80x94R13; xe2x80x94NR15R15xe2x80x2; 
When Z is cycloalkyl or heterocycloalkyl, preferred is where Z is an optionally substituted piperidine or piperazine.
When Z is xe2x80x94Lxe2x80x94(CR12R12xe2x80x2)axe2x80x94R13, a is 0, 1, 2, 3 or 4, preferably 0 or 1. L is selected from xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 and xe2x80x94S(O2)xe2x80x94; preferred is where L is xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, xe2x80x94Nxe2x95x90Nxe2x80x94, xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94; more preferred is where L is xe2x80x94Cxe2x89xa1Cxe2x80x94, xe2x80x94CHxe2x95x90CHxe2x80x94, or xe2x80x94Nxe2x95x90Nxe2x80x94. Each R12 and R12xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; preferably each R12 is hydrogen and each R12xe2x80x2 is independently hydrogen or lower alkyl R13 is selected from aryl, heteroaryl, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, heterocycloalkyl and cycloalkyl; preferably R13 is aryl, heteroaryl, heterocycloalkyl or cycloalkyl. However, if L is xe2x80x94Cxe2x89xa1Cxe2x80x94 or xe2x80x94CHxe2x95x90CHxe2x80x94, then R13 may also be selected from xe2x80x94C(O)NR14R14xe2x80x2 where (i) R14 and R14xe2x80x2 are independently selected from hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl, or (ii) R14 and R14xe2x80x2, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) ring atoms of which from 1 to 3 (preferably 1 or 2) are heteroatoms.
When Z is xe2x80x94NR15R15xe2x80x2, R15 and R15xe2x80x2 each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, heteroalkyl, and xe2x80x94C(O)xe2x80x94Qxe2x80x94(CR16R16xe2x80x2)bxe2x80x94R17; preferably R15 and R15xe2x80x2 are independently selected from hydrogen, alkyl, aryl and xe2x80x94C(O)xe2x80x94Qxe2x80x94(CR16R16xe2x80x2)bxe2x80x94R17. When R15 and/or R15xe2x80x2 is xe2x80x94C(O)xe2x80x94Qxe2x80x94(CR16R16xe2x80x2)bxe2x80x94R17, b is 0, 1, 2, 3 or 4; b is preferably 0 or 1. Q is selected from a covalent bond and xe2x80x94NR18xe2x80x94; Q is preferably a covalent bond. Each R16 and R16xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; preferably each R16 is hydrogen and each R16xe2x80x2 is independently hydrogen or lower alkyl. R17 and R18 each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl (preferably one is aryl); or R17 and R18, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) ring atoms of which from 1 to 3 (preferably 1 or 2) are heteroatoms; preferably R17 is alkyl, aryl, heteroaryl, cycloalkyl or heterocycloalkyl. Alternatively, R15 and R18, together with the nitrogen atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) ring atoms of which from 1 to 3 (preferably 1 or 2) are heteroatoms. Most preferred is where R15 is hydrogen or lower alkyl and R15xe2x80x2 is xe2x80x94C(O)xe2x80x94Qxe2x80x94(CR16R16xe2x80x2)bxe2x80x94R17 where Q is a covalent bond, b=0, and R17 is aryl.
Alternatively, R15 and R15xe2x80x2, together with the nitrogen atom to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) ring atoms of which from 1 to 3 (preferably 1 or 2) are heteroatoms.
When Z is 
(referred to herein as Formula (A)), Exe2x80x2 and Mxe2x80x2 are independently selected from xe2x80x94CHxe2x80x94 and xe2x80x94Nxe2x80x94; preferred is where Exe2x80x2 is xe2x80x94CH and Mxe2x80x2 is xe2x80x94CH. Lxe2x80x2 is selected from xe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94N(R20)xe2x80x94, xe2x80x94C(R20)xe2x95x90C(R20xe2x80x2)xe2x80x94, xe2x80x94Nxe2x95x90C(R20)xe2x80x94, and xe2x80x94Nxe2x95x90Nxe2x80x94; preferably L is xe2x80x94C(R20)xe2x95x90C(R20xe2x80x2)xe2x80x94. R20 and R20xe2x80x2 each is independently selected from hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; preferably hydrogen or lower alkyl. c is 0, 1, 2, 3 or 4, preferably 0 or 1. Each R19 and R19xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, and alkoxy; preferably each R19 is hydrogen and each R19xe2x80x2 is independently hydrogen or lower alkyl. Axe2x80x2 is selected from a covalent bond, xe2x80x94Oxe2x80x94, xe2x80x94SOdxe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94C(O)N(R21)xe2x80x94, xe2x80x94N(R21)xe2x80x94, and xe2x80x94N(R21)C(O)xe2x80x94; preferably Axe2x80x2 is xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94. d is 0, 1 or 2. R21 is selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, and haloalkyl; R21 is preferably lower alkyl or aryl. Gxe2x80x2 is xe2x80x94(CR22R22xe2x80x2)exe2x80x94R23. e is 0, 1, 2, 3 or 4, preferably 0 or 1. Each R22 and R22xe2x80x2 is independently selected from hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, heterocycloalkyl, halogen, haloalkyl, hydroxy, alkoxy and aryloxy; preferably each R22 is hydrogen and each R22xe2x80x2 is independently hydrogen or lower alkyl. R23 is selected from hydrogen, alkyl, alkenyl, alkynyl, halogen, heteroalkyl, haloalkyl, aryl, heteroaryl, cycloalkyl, and heterocycloalkyl; preferably R23 is lower alkyl or aryl. Alternatively, R21 and R23, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) atoms of which 1 to 3 (preferably 1 or 2) are heteroatoms. Alternatively, R20 and R23, together with the atoms to which they are bonded, join to form an optionally substituted heterocyclic ring containing from 5 to 8 (preferably 5 or 6) atoms of which 1 to 3 (preferably 1 or 2) are heteroatoms.
Most preferred compounds are those where Z is xe2x80x94NR15R15xe2x80x2 or 
Preferred sub-genuses of compounds are those carboxylic acid-containing compounds having a structure according to the following Formula (II) or Formula (III) 
where R6, X, k, l, E, A, G, and Z are as described with respect to Formula (I).
The compounds of the invention can be prepared using a variety of procedures. The starting materials used in preparing the compounds of the invention are known, made by known methods, or are commercially available. Particularly preferred syntheses are described in the following general reaction schemes. (The R groups used to illustrate the reaction schemes do not necessarily correlate to the respective R groups used to describe the various aspects of the Formula I compounds. That is, for example, R1 in Formula (I) does not represent the same moiety as R1 here). Specific examples for making the compounds of the present invention are set forth in Section VIII, below. 
In Scheme 1, the aldehyde S1a is a commercially available material. Its synthetic utility has widely been recognized and several conditions have been developed for its stereoselective reactions with nucleophiles. This way, various aryl or alkyl R1 groups can be introduced to form alcohols S1b, and the syn/anti stereochmistry can be controlled depending on the reaction conditions. The newly formed hydroxyl group of S1b can, in turn, be functionalized by a wide variety of alkylating agents using methods well known to the skilled artisan to introduce substituent R2. The product S1c can then be converted to the target carboxylic acid using methods well documented in the chemical literature. Thus, the Boc and the acetonide protective groups of S1c can be removed under acidic conditions to obtain the aminoalcohol S1d. The amino group of this intermediate can selectively be derivatized by an appropriate aryl sulfonyl chloride using standard Shott and Bouman conditions to give sulfonamide S1e. Further elaboration of the aryl group R3 may be performed at this stage using, for example, the Suzuki coupling method. Finally, the alcohol function is converted to the carboxylic acid using standard oxidation methods to produce the target molecule S1f.
If desired, the carboxylic acid functionality in compounds of type S1f can be converted to the hydroxamic acid by coupling with hydroxylamine using a mixed anhydride method or by forming of an intermediate acid chloride. 
In Scheme 2, the commercially available epoxy-alcohol S2a is converted to the aziridine ester S2e using known methodology (Zwanenburg et. al., Rec. Trav. Chim. Pay. Bas 1992, 111, 1). First, the alcohol is oxidized and the resulting carboxylic acids S2b is esterified to give the epoxyester S2c. The epoxide ring of S2c can then be opened in the reaction with sodium azide in the presence of ammonium chloride to give the azido-alcohol S2d as a mixture of regioisomers. The aziridine S2e, which can be obtained from S2d upon treatment with triphenylphosphine, has been shown in chemical literature to be a highly versatile electrophile capable of undergoing ring opening reactions with various sulfur-, oxygen- and nitrogen-based nucleophiles. For example, thiols react with S2e under the catalysis of boron trifluoride etherate to give functionalized amino-acid S2f (Xxe2x95x90S) in very good yields. Similarily, oxygen or nitrogen functionalized amino-acids S2f (Xxe2x95x90O or N) can be prepared through acetic acid or azide addition, respectively (Legtersen, J. et. al., Rec. Trav. Chim. Pay. Bas 1992, 111, 59). The free amino group can then be derivatized with various sulfonyl chlorides to give sulfonamide esters S2g. If necessary, a more complex aryl sulfonyl group can be introduced in a sequence of several synthetic steps. Finally, the ester function is converted to the carboxylic acid using one of the standard hydrolysis methods to produce the target molecule S2h.
If desired, the ester functionality in compounds of type S2g can be converted to the hydroxamic acid by reaction with hydroxylamine under alkaline conditions. 
In Scheme 3, well known Evans chemistry is utilized to establish absolute and relative stereochemistry of chiral centers of the target aminoalcohol S3d. Thus, the oxazolidinone bromoacetate S3a is reacted with a selected aldehyde to obtain a bromoalcohol S3b with very high stereoselectivity. In the following step, standard conditions of SN2 substitution are applied and the bromide atom is replaced by azide to give an intermediate S3c. Hydrolysis of the oxazolidinone group can be performed utilizing conditions well described in the chemical literature to produce a key intermediate aminoacid S3d. The free amino group of S3d can then be derivatized with various sulfonyl chlorides to give the target inhibitors S3e. If necessary, a more complex aryl sulfonyl groups can be introduced in a sequence of several synthetic steps. If desired, the carboxylic acid functionality in compounds of type S3e can be converted to the hydroxamic acid by coupling with hydroxylamine using a mixed anhydride method or by forming of an intermediate acid chloride.
These steps may be varied to increase yield of desired product. The skilled artisan will recognize the judicious choice of reactants, solvents, and temperatures is an important component in any successful synthesis. Determination of optimal conditions, etc. is routine. Thus, the skilled artisan can make a variety of compounds using the guidance of the schemes above.
It is recognized that the skilled artisan in the art of organic chemistry can readily carry out standard manipulations of organic compounds without further direction; that is, it is well within the scope and practice of the skilled artisan to carry out such manipulations. These include, but are not limited to, reduction of carbonyl compounds to their corresponding alcohols, oxidations of hydroxyls and the like, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. Examples of these manipulations are discussed in standard texts such as March, Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (Vol. 2) and other art that the skilled artisan is aware of.
The skilled artisan will also readily appreciate that certain reactions are best carried out when another potentially reactive functionality on the molecule is masked or protected, thus avoiding any undesirable side reactions and/or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many of these manipulations can be found for example in T. Greene, Protecting Groups in Organic Synthesis. Of course, amino acids used as starting materials with reactive side chains are preferably blocked to prevent undesired side reactions.
The compounds of the invention may have one or more chiral centers. As a result, one may selectively prepare one optical isomer, including diastereomer and enantiomer, over another, for example by chiral starting materials, catalysts or solvents, or may prepare both stereoisomers or both optical isomers, including diastereomers and enantiomers at once (a racemic mixture). Since the compounds of the invention may exist as racemic mixtures, mixtures of optical isomers, including diastereomers and enantiomers, or stereoisomers may be separated using known methods, such as chiral salts, chiral chromatography and the like.
In addition, it is recognized that one optical isomer, including diastereomer and enantiomer, or stereoisomer may have favorable properties over the other. Thus when disclosing and claiming the invention, when one racemic mixture is disclosed, it is clearly contemplated that both optical isomers, including diastereomers and enantiomers, or stereoisomers substantially free of the other are disclosed and claimed as well.
Metalloproteases (MPs) found in the body operate, in part, by breaking down the extracellular matrix, which comprises extracellular proteins and glycoproteins. Inhibitors of metalloproteases are useful in treating diseases caused, at least in part, by the breakdown of such proteins and glycoproteins. These proteins and glycoproteins play an important role in maintaining the size, shape, structure and stability of tissue in the body. Thus, MPs are intimately involved in tissue remodeling.
As a result of this activity, MPs have been said to be active in many disorders involving either the: (1) breakdown of tissues including opthalmic diseases; degenerative diseases, such as arthritis, multiple sclerosis and the like; and metastasis or mobility of tissues in the body; or (2) remodeling of tissues including cardiac disease, fibrotic disease, scarring, benign hyperplasia, and the like.
The compounds of the present invention prevent or treat disorders, diseases and/or unwanted conditions that are characterized by unwanted or elevated activity by MPs. For example, the compounds can be used to inhibit MPs which:
1. destroy structural proteins (i.e. the proteins that maintain tissue stability and structure);
2. interfere in inter/intracellular signaling, including those implicated in cytokine up-regulation, and/or cytokine processing and/or inflammation, tissue degradation and other maladies [Mohler K M, et al, Nature 370 (1994) 218-220, Gearing A J H, et al, Nature 370 (1994) 555-557 McGeehan G M, et al, Nature 370(1994) 558-561]; and
3. facilitate processes which are undesired in the subject being treated, for example, the processes of sperm maturation, egg fertilization and the like.
As used herein, an xe2x80x9cMP related disorderxe2x80x9d or xe2x80x9cMP related diseasexe2x80x9d is one that involves unwanted or elevated MP activity in the biological manifestation of the disease or disorder; in the biological cascade leading to the disorder; or as a symptom of the disorder. This xe2x80x9cinvolvementxe2x80x9d of the MP includes:
1. The unwanted or elevated MP activity as a xe2x80x9ccausexe2x80x9d of the disorder or biological manifestation, whether the activity is elevated genetically, by infection, by autoimmunity, trauma, biomechanical causes, lifestyle [e.g. obesity] or by some other cause;
2. The MP as part of the observable manifestation of the disease or disorder. That is, the disease or disorder is measurable in terms of the increased MP activity. From a clinical standpoint, unwanted or elevated MP levels indicate the disease; however, MPs need not be the xe2x80x9challmarkxe2x80x9d of the disease or disorder; or
3. The unwanted or elevated MP activity is part of the biochemical or cellular cascade that results or relates to the disease or disorder. In this respect, inhibition of the MP activity interrupts the cascade, and thus controls the disease.
The term xe2x80x9ctreatmentxe2x80x9d is used herein to mean that, at a minimum, administration of a compound of the present invention mitigates a disease associated with unwanted or eleveated MP activity in a mammalian subject, preferably in humans. Thus, the term xe2x80x9ctreatmentxe2x80x9d includes: preventing an MP-mediated disease from occurring in a mammal, particularly when the mammal is predisposed to acquiring the disease, but has not yet been diagnosed with the disease; inhibiting the MP-mediated disease; and/or alleviating the MP-mediated disease. Insofar as the methods of the present invention are directed to preventing disease states associated with unwanted MP activity, it is understood that the term xe2x80x9cpreventxe2x80x9d does not require that the disease state be completely thwarted. (See Webster""s Ninth Collegiate Dictionary.) Rather, as used herein, the term preventing refers to the ability of the skilled artisan to identify a population that is susceptible to MP-related disorders, such that administration of the compounds of the present invention may occur prior to onset of the disease. The term does not imply that the disease state be completely avoided. For example, osteoarthritis (OA) is the most common rhueumatological disease with some joint changes radiologically detectable in 80% of people over 55 years of age. Fife, R. S., xe2x80x9cA Short History of Osteoarthritisxe2x80x9d, Osteoarthritis: Diagnosis and Medical/Surgical Management, R. W. Moskowitz, D. S. Howell, V. M. Goldberg and H. J. Mankin Eds., p 11-14 (1992). A common risk factor that increases the incidence of OA is traumatic injury of the joint. Surgical removal of the meniscus following knee injury increases the risk of radiographically detectable OA and this risk increases with time. Roos, H et al. xe2x80x9cKnee Osteoarthritis After Menisectomy: Prevalence of Radiographic Changes After Twenty-one Years, Compared with Matched Controls.xe2x80x9d Arthritis Rheum., Vol. 41, pp 687-693; Roos, H et al. xe2x80x9cOsteoarthritis of the Knee After Injury to the Anterior Cruciate Ligament or Meniscus: The Influence of Time and Age.xe2x80x9d Osteoarthritis Cartilege., Vol. 3, pp 261-267 (1995). Thus, this patient population is identifiable and could receive administration of a compound of the present invention before progression of the disease. Thus, progression of OA in such individuals would be xe2x80x9cpreventedxe2x80x9d.
Advantageously, many MPs are not distributed evenly throughout the body. Thus, the distribution of MPs expressed in various tissues are often specific to those tissues. For example, the distribution of metalloproteases implicated in the breakdown of tissues in the joints is not the same as the distribution of metalloproteases found in other tissues. Though not essential for activity or efficacy, certain diseases, disorders, and unwanted conditions preferably are treated with compounds that act on specific MPs found in the affected tissues or regions of the body. For example, a compound which displays a higher degree of affinity and inhibition for an MP found in the joints (e.g. chondrocytes) would be preferred for treatment of a disease, disorder, or unwanted condition found there than other compounds which are less specific.
In addition, certain inhibitors are more bioavailable to certain tissues than others. Choosing an MP inhibitor which is more bioavailable to a certain tissue and which acts on the specific MPs found in that tissue, provides for specific treatment of the disease, disorder, or unwanted condition. For example, compounds of this invention vary in their ability to penetrate into the central nervous system. Thus, compounds may be selected to produce effects mediated through MPs found specifically outside the central nervous system.
Determination of the specificity of an inhibitor of a specific MP is within the skill of the artisan in that field. Appropriate assay conditions can be found in the literature. Specifically, assays are known for stromelysin and collagenase. For example, U.S. Pat. No. 4,743,587 references the procedure of Cawston, et al., Anal Biochem (1979) 99:340-345. See also, Knight, C. G. et al., xe2x80x9cA Novel Coumarin-Labelled Peptide for Sensitive Continuous Assays of the Matrix Metalloproteasesxe2x80x9d, FEBS Letters, Vol. 296, pp. 263-266 (1992). The use of a synthetic substrate in an assay is described by Weingarten, H., et al., Biochem Biophy Res Comm (1984) 139:1184-1187. Any standard method for analyzing the breakdown of structural proteins by MPs can, of course, be used. The ability of compounds of the invention to inhibit metalloprotease activity can be tested in the assays found in the literature, or variations thereof. Isolated metalloprotease enzymes can be used to confirm the inhibiting activity of the invention compounds, or crude extracts which contain the range of enzymes capable of tissue breakdown can be used.
The compounds of this invention are also useful for prophylactic or acute treatment. They are administered in any way the skilled artisan in the fields of medicine or pharmacology would desire. It is immediately apparent to the skilled artisan that preferred routes of administration will depend upon the disease state being treated and the dosage form chosen. Preferred routes for systemic administration include administration perorally or parenterally.
However, the skilled artisan will readily appreciate the advantage of administering the MP inhibitor directly to the affected area for many diseases, disorders, or unwanted conditions. For example, it may be advantageous to administer MP inhibitors directly to the area of the disease, disorder, or unwanted condition such as in the area affected by surgical trauma (e. g., angioplasty), scarring, burning (e.g., topical to the skin), or for opthalmic and periodontal indications.
Because the remodeling of bone involves MPs, the compounds of the invention are useful in preventing prosthesis loosening. It is known in the art that over time prostheses loosen, become painful, and may result in further bone injury, thus demanding replacement. The need for replacement of such prostheses includes those such as in joint replacements (for example hip, knee and shoulder replacements), dental prosthesis, including dentures, bridges and prosthesis secured to the maxilla and/or mandible.
MPs are also active in remodeling of the cardiovascular system (for example, in congestive heart failure). It has been suggested that one of the reasons angioplasty has a higher than expected long term failure rate (reclosure over time) is that MP activity is not desired or is elevated in response to what may be recognized by the body as xe2x80x9cinjuryxe2x80x9d to the basement membrane of the vessel. Thus regulation of MP activity in indications such as dilated cardiomyopathy, congestive heart failure, atherosclerosis, plaque rupture, reperfusion injury, ischemia, chronic obstructive pulmonary disease, angioplasty restenosis and aortic aneurysm may increase long term success of any other treatment, or may be a treatment in itself.
In skin care, MPs are implicated in the remodeling or xe2x80x9cturnoverxe2x80x9d of skin. As a result, the regulation of MPs improves treatment of skin conditions including but not limited to, wrinkle repair, regulation and prevention and repair of ultraviolet induced skin damage. Such a treatment includes prophylactic treatment or treatment before the physiological manifestations are obvious. For example, the MP may be applied as a pre-exposure treatment to prevent ultaviolet damage and/or during or after exposure to prevent or minimize post-exposure damage. In, addition, MPs are implicated in skin disorders and diseases related to abnormal tissues that result from abnormal turnover, which includes metalloprotease activity, such as epidermolysis bullosa, psoriasis, scleroderma and atopic dermatitis. The compounds of the invention are also useful for treating the consequences of xe2x80x9cnormalxe2x80x9d injury to the skin including scarring or xe2x80x9ccontractionxe2x80x9d of tissue, for example, following burns. MP inhibition is also useful in surgical procedures involving the skin for prevention of scarring, and promotion of normal tissue growth including in such applications as limb reattachment and refractory surgery (whether by laser or incision).
In addition, MPs are related to disorders involving irregular remodeling of other tissues, such as bone, for example, in otosclerosis and/or osteoporosis, or for specific organs, such as in liver cirrhosis and fibrotic lung disease. Similarly, in diseases such as multiple sclerosis, MPs may be involved in the irregular modeling of blood brain barrier and/or myelin sheaths of nervous tissue. Thus, regulating MP activity may be used as a strategy in treating, preventing, and controlling such diseases.
MPs are also thought to be involved in many infections, including cytomegalovirus (CMV); retinitis; HIV, and the resulting syndrome, AIDS.
MPs may also be involved in extra vascularization where surrounding tissue needs to be broken down to allow new blood vessels such as in angiofibroma and hemangioma.
Since MPs break down the extracellular matrix, it is contemplated that inhibitors of these enzymes can be used as birth control agents, for example in preventing ovulation, in preventing penetration of the sperm into and through the extracellular milieu of the ovum, implantation of the fertilized ovum and in preventing sperm maturation.
Additionally, they are also contemplated to be useful in preventing or stopping premature labor and delivery.
Since MPs are implicated in the inflammatory response and in the processing of cytokines, the compounds are also useful as anti-inflammatories, for use in disease where inflammation is prevalent including, inflammatory bowel disease, Crohn""s disease, ulcerative colitis, pancreatitis, diverticulitis, asthma or related lung disease, rheumatoid arthritis, gout and Reiter""s Syndrome.
Where autoimmunity is the cause of the disorder, the immune response often triggers MP and cytokine activity. Regulation of MPs in treating such autoimmune disorders is a useful treatment strategy. Thus MP inhibitors can be used for treating disorders including, lupus erythmatosis, ankylosing spondylitis, and autoimmune keratitis. Sometimes the side effects of autoimmune therapy result in exacerbation of other conditions mediated by MPs, here MP inhibitor therapy is effective as well, for example, in autoimmune-therapy-induced fibrosis.
In addition, other fibrotic diseases lend themselves to this type of therapy, including pulmonary disease, bronchitis, emphysema, cystic fibrosis, acute respiratory distress syndrome (especially the acute phase response).
Where MPs are implicated in the undesired breakdown of tissue by exogenous agents, these can be treated with MP inhibitors. For example, they are effective as rattle snake bite antidote, as anti-vessicants, in treating allergic inflammation, septicemia and shock. In addition, they are useful as antiparasitics (e.g., in malaria) and antiinfectives. For example, they are thought to be useful in treating or preventing viral infection, including infection which would result in herpes, xe2x80x9ccoldxe2x80x9d (e.g., rhinoviral infection), meningitis, hepatitis, HIV infection and AIDS.
MP inhibitors are also thought to be useful in treating Alzheimer""s disease, amyotrophic lateral sclerosis (ALS), muscular dystrophy, complications resulting from or arising out of diabetes, especially those involving loss of tissue viability, coagulation, Graft vs. Host disease, leukemia, cachexia, anorexia, proteinuria, and regulation of hair growth.
For some diseases, conditions or disorders MP inhibition is contemplated to be a preferred method of treatment. Such diseases, conditions or disorders include, arthritis (including osteoarthritis and rheumatoid arthritis), cancer (especially the prevention or arrest of tumor growth and metastasis), ocular disorders (especially corneal ulceration, lack of corneal healing, macular degeneration, and pterygium), and gum disease (especially periodontal disease, and gingivitis)
Compounds preferred for, but not limited to, the treatment of arthritis (including osteoarthritis and rheumatoid arthritis) are those compounds that are selective for the matrix metalloproteases and the disintegrin metalloproteases. Compounds preferred for, but not limited to, the treatment of cancer (especially the prevention or arrest of tumor growth and metastasis) are those compounds that preferentially inhibit gelatinases or type IV collagenases. Compounds preferred for, but not limited to, the treatment of ocular disorders (especially corneal ulceration, lack of corneal healing, macular degeneration, and pterygium) are those compounds that broadly inhibit metalloproteases. Preferably these compounds are administered topically, more preferably as a drop or gel. Compounds preferred for, but not limited to, the treatment of gum disease (especially periodontal disease, and gingivitis) are those compounds that preferentially inhibit collagenases.
The compositions of the invention comprise:
(a) a safe and effective amount of a compound of the invention; and
(b) a pharmaceutically-acceptable carrier.
As discussed above, numerous diseases are known to be mediated by excess or undesired metalloprotease activity. These include tumor metastasis, osteoarthritis, rheumatoid arthritis, skin inflammation, ulcerations, particularly of the cornea, reaction to infection, periodontitis and the like. Thus, the compounds of the invention are useful in therapy with regard to conditions involving this unwanted activity.
The invention compounds can therefore be formulated into pharmaceutical compositions for use in treatment or prophylaxis of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington""s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., latest edition.
A xe2x80x9csafe and effective amountxe2x80x9d of a Formula (I) compound is an amount that is effective, to inhibit metalloproteases at the site(s) of activity in an animal, preferably a mammal, more preferably a human subject, without undue adverse side effects (such as toxicity, irritation, or allergic response), commensurate with a reasonable benefit/risk ratio when used in the manner of this invention. The specific xe2x80x9csafe and effective amountxe2x80x9d will, obviously, vary with such factors as the particular condition being treated, the physical condition of the patient, the duration of treatment, the nature of concurrent therapy (if any), the specific dosage form to be used, the carrier employed, the solubility of the Formula (I) compound therein, and the dosage regimen desired for the composition.
In addition to the subject compound, the compositions of the subject invention contain a pharmaceutically-acceptable carrier. The term xe2x80x9cpharmaceutically-acceptable carrierxe2x80x9d, as used herein, means one or more compatible solid or liquid filler diluents or encapsulating substances which are suitable for administration to an animal, preferably a mammal, more preferably a human. The term xe2x80x9ccompatiblexe2x80x9d, as used herein, means that the components of the composition are capable of being commingled with the subject compound, and with each other, in a manner such that there is no interaction which would substantially reduce the pharmaceutical efficacy of the composition under ordinary use situations. Pharmaceutically-acceptable carriers must, of course, be of sufficiently high purity and sufficiently low toxicity to render them suitable for administration to the subject being treated. The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is determined in-part by the way the compound is to be administered.
Some examples of substances which can serve as pharmaceutically-acceptable carriers or components thereof are sugars, such as lactose, glucose and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the Tweens(copyright); wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents; stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.
Pharmaceutically-acceptable carriers for systemic adminisitration include sugars, starches, cellulose and its derivatives, malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils, polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonic saline, and pyrogen-free water. Preferred carriers for parenteral administration include propylene glycol, ethyl oleate, pyrrolidone, ethanol, and sesame oil. Preferably, the pharmaceutically-acceptable carrier, in compositions for parenteral administration, comprises at least about 90% by weight of the total composition. If the subject compound is to be injected, the preferred pharmaceutically-acceptable carrier is sterile, physiological saline, with a blood-compatible suspending agent, the pH of which has preferably been adjusted to about 7.4.
The compositions of this invention are preferably provided in unit dosage form. As used herein, a xe2x80x9cunit dosage formxe2x80x9d is a composition of this invention containing an amount of a Formula (I) compound that is suitable for administration to an animal, preferably a mammal, more preferably a human subject, in a single dose, according to good medical practice. These compositions preferably contain from about 5 mg (milligrams) to about 1000 mg, more preferably from about 10 mg to about 500 mg, more preferably from about 10 mg to about 300 mg, of a Formula (I) compound.
The compositions of this invention may be in any of a variety of forms, suitable (for example) for oral, rectal, topical, nasal, ocular or parenteral administration. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. These include solid or liquid fillers, diluents, hydrotropes, surface-active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the Formula (I) compound. The amount of carrier employed in conjunction with the Formula (I) compound is sufficient to provide a practical quantity of material for administration per unit dose of the Formula (I) compound. Techniques and compositions for making dosage forms useful in the methods of this invention are described in the following references, all incorporated by reference herein: Modern Pharmaceutics, Chapters 9 and 10 (Banker and Rhodes, editors, 1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).
Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. These oral forms comprise a safe and effective amount, usually at least about 5%, and preferably from about 25% to about 50%, of the Formula (I) compound. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow-inducing agents, and/or melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and/or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules. Such liquid dose forms will optionally contain suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.
The pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration are well-known in the art. Tablets typically comprise conventional pharmaceutically-compatible adjuvants as inert diluents such as calcium carbonate, sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and sucrose; disintegrants such as starch, alginic acid and croscarmelose; and lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the FDandC dyes, can be added for appearance. Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of the subject invention, and can be readily made by a person skilled in the art.
Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol and water. For a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, Avicel(copyright) RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as the sweeteners, flavoring agents and colorants disclosed above.
Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit(copyright) coatings, waxes and shellac.
Compositions of the subject invention may optionally include other drug actives.
Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose and hydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.
The compositions of this invention can also be administered topically to a subject, e.g., by the direct laying on or spreading of the composition on the epidermal or epithelial tissue of the subject, or transdermally via a xe2x80x9cpatchxe2x80x9d. Such compositions include, for example, lotions, creams, solutions, gels and solids. These topical compositions preferably comprise a safe and effective amount, usually at least about 0.1%, and preferably from about 1% to about 5%, of the Formula (I) compound. Suitable carriers for topical administration preferably remain in place on the skin as a continuous film, and resist being removed by perspiration or immersion in water. Generally, the carrier is organic in nature and capable of having dispersed or dissolved therein the Formula (I) compound. The carrier may include pharmaceutically-acceptable emollients, emulsifiers, thickening agents, solvents and the like.
This invention also provides methods of treating disorders associated with excess or undesired metalloprotease activity in a human or other animal subject, by administering a safe and effective amount of a Formula (I) compound to said subject. As used herein, a xe2x80x9cdisorder associated with excess or undesired metalloprotease activityxe2x80x9d is any disorder characterized by degradation of matrix proteins. The methods of the invention are useful in treating disorders described above.
As indicated, compositions of this invention can be administered topically or systemically. Systemic application includes any method of introducing Formula (I) compound into the tissues of the body, e.g., intra-articular (especially in treatment of rheumatoid arthritis), intrathecal, epidural, intramuscular, transdermal, intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oral administration. The Formula (I) compounds of the present invention are preferably administered orally.
The specific dosage of compound to be administered, as well as the duration of treatment and whether the treatment is topical or systemic, are interdependent. The dosage and treatment regimen will also depend upon such factors as the specific Formula (I) compound used, the treatment indication, the ability of the Formula (I) compound to reach minimum inhibitory concentrations at the site of the metalloprotease to be inhibited, the personal attributes of the subject (such as weight), compliance with the treatment regimen, and the presence and severity of any side effects of the treatment.
Typically, for a human adult (weighing approximately 70 kilograms), from about 5 mg to about 3000 mg, more preferably from about 5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg, of Formula (I) compound are administered per day for systemic administration. It is understood that these dosage ranges are by way of example only, and that daily administration can be adjusted depending on the factors listed above.
A preferred method of administration for treatment of rheumatoid arthritis is oral or parenteral dosing via intra-articular injection. As is known and practiced in the art, all formulations for parenteral administration must be sterile. For mammals, especially humans, (assuming an approximate body weight of 70 kilograms) individual doses of from about 10 mg to about 1000 mg are preferred.
A preferred method of systemic administration is oral. Individual doses of from about 10 mg to about 1000 mg, preferably from about 10 mg to about 300 mg are preferred.
Topical administration can be used to deliver the Formula (I) compound systemically, or to treat a subject locally. The amounts of Formula (I) compound to be topically administered depends upon such factors as skin sensitivity, type and location of the tissue to be treated, the composition and carrier (if any) to be administered, the particular Formula (I) compound to be administered, as well as the particular disorder to be treated and the extent to which systemic (as distinguished from local) effects are desired.
The compounds of the invention can be targeted to specific locations where the metalloprotease is accumulated by using targeting ligands. For example, to direct the compounds to metalloproteases contained in a tumor, the compound is conjugated to an antibody or fragment thereof which is immunoreactive with a tumor marker, as is generally understood in the preparation of immunotoxins in general. The targeting ligand can also be a ligand suitable for a receptor which is present on the tumor. Any targeting ligand which specifically reacts with a marker for the intended target tissue can be used. Methods for coupling the invention compound to the targeting ligand are well known and are similar to those described below for coupling to carriers. The conjugates are formulated and administered as described below.
For localized conditions, topical administration is preferred. For example, to treat ulcerated cornea, direct application to the affected eye may employ a formulation as eyedrops or aerosol. For corneal treatment, the compounds of the invention can also be formulated as gels, drops or ointments, or can be incorporated into collagen or a hydrophilic polymer shield. The materials can also be inserted as a contact lens or reservoir or as a subconjunctival formulation. For treatment of skin inflammation, the compound is applied locally and topically in a gel, paste, salve or ointment. For treatment of oral diseases, the compound may be applied locally in a gel, paste, mouth wash, or implant. The mode of treatment thus reflects the nature of the condition and suitable formulations for any selected route are available in the art.
In all of the foregoing, of course, the compounds of the invention can be administered alone or as mixtures, and the compositions may further include additional drugs or excipients as appropriate for the indication.
Some of the compounds of the invention also inhibit bacterial metalloproteases. Some bacterial metalloproteases may be less dependent on the stereochemistry of the inhibitor, whereas substantial differences are found between diastereomers in their ability to inactivate the mammalian proteases. Thus, this pattern of activity can be used to distinguish between the mammalian and bacterial enzymes.
Metalloproteases active at a particularly undesired location (e.g., an organ or certain types of cells) can be targeted by conjugating the compounds of the invention to a targeting ligand specific for a marker at that location such as an antibody or fragment thereof or a receptor ligand. Conjugation methods are known in the art.
The invention is also directed to various other processes which take advantage of the unique properties of these compounds. Thus, in another aspect, the invention is directed to the compounds of Formula (I) conjugated to solid supports. These conjugates can be used as affinity reagents for the purification of a desired metalloprotease.
In another aspect, the invention is directed to the compounds of Formula (I) conjugated to label. As the compounds of the invention bind to at least one metalloprotease, the label can be used to detect the presence of relatively high levels of metalloprotease in vivo or in vitro cell culture.
In addition, the compounds of Formula (I) can be conjugated to carriers which permit the use of these compounds in immunization protocols to prepare antibodies specifically immunoreactive with the compounds of the invention. Typical conjugation methods are known in the art. These antibodies are then useful both in therapy and in monitoring the dosage of the inhibitors.
The invention compounds can also be coupled to labels such as scintigraphic labels, e.g., technetium 99 or 1-131, using standard coupling methods. The labeled compounds are administered to subjects to determine the locations of excess amounts of one or more metalloproteases in vivo. The ability of the inhibitors to selectively bind metalloprotease is thus taken advantage of to map the distribution of these enzymes in situ. The techniques can also be employed in histological procedures and the labeled invention compounds can be used in competitive immunoassays.